rs556646437

Variant names:

• chr1-205065879-G-A
• rs556646437
• NM_005076.5:c.1786G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005076.5(CNTN2):​c.1786G>A​(p.Ala596Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000451 in 1,598,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A596V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.69
• Publications: 0 publications found

Genes affected

CNTN2 (HGNC:2172): (contactin 2) This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

CNTN2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, familial adult myoclonic, 5

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign adult familial myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019926041).
• BP6: Variant 1-205065879-G-A is Benign according to our data. Variant chr1-205065879-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474468.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000267 (4/150034) while in subpopulation SAS AF = 0.000838 (4/4772). AF 95% confidence interval is 0.000286. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005076.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	NM_005076.5	MANE Select	c.1786G>A	p.Ala596Thr	missense	Exon 14 of 23	NP_005067.1	Q02246
	CNTN2	NM_001346083.2		c.1786G>A	p.Ala596Thr	missense	Exon 14 of 23	NP_001333012.1	Q02246
	CNTN2	NR_144350.2		n.2055G>A		non_coding_transcript_exon	Exon 14 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.1786G>A	p.Ala596Thr	missense	Exon 14 of 23	ENSP00000330633.4	Q02246
	CNTN2	ENST00000640428.1	TSL:5	c.1786G>A	p.Ala596Thr	missense	Exon 14 of 23	ENSP00000491474.1	A0A1W2PQ11
	CNTN2	ENST00000853779.1		c.1837G>A	p.Ala613Thr	missense	Exon 15 of 24	ENSP00000523838.1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 4 AN: 149916 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000918 AC: 23 AN: 250422 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000470 AC: 68 AN: 1448036 Hom.: 0 Cov.: 34 AF XY: 0.0000527 AC XY: 38 AN XY: 720758

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000513 AC: 44 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1101796

Other (OTH) AF: 0.000202 AC: 12 AN: 59516

GnomAD4 genome AF: 0.0000267 AC: 4 AN: 150034 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73306

African (AFR) AF: 0.00 AC: 0 AN: 41222

American (AMR) AF: 0.00 AC: 0 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000838 AC: 4 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66964

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.0000812 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, familial adult myoclonic, 5 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.92	L
PhyloP100		3.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.045
Sift	Benign	0.43	T
Sift4G	Benign	0.50	T
Polyphen		0.0040	B
Vest4		0.32
MutPred		0.47		Gain of phosphorylation at A596 (P = 0.0169)
MVP		0.76
MPC		0.43
ClinPred		0.052	T
GERP RS		3.5
PromoterAI		0.034	Neutral
Varity_R		0.051
gMVP		0.25
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs556646437; hg19: chr1-205035007; COSMIC: COSV100084861; COSMIC: COSV100084861;